The tridecapeptide, neurotensin (NT) is known to have a wide variety of pharmacological effects, including those common to peptides in the kinen group. NT is also known to have activity within the central nervous system producing hypothermia, a reduction in locomotor activity and an antinocisponsive effect in rodents. These pharmacological actions of NT suggest that the peptide is a neurotransmitter or neuromodulator. Consequently, this tridecapeptide holds a great deal of potential for a host of therapeutic applications.
A solid-phase method for preparing peptides, including NT, and analogs of NT modified at the C-terminal end of the molecule is described by St. Pierre, et al. [J. Med. Chem., 24, 370-376 (1981)].
The structural requirements for biological activity of NT and methods for obtaining partial sequences of this tridecapeptide have been reported by R. Carraway, et al., [J. Biol. Chem., 251, 7035-7044 (1976)].
The binding affinity of NT and NT analogs has been examined by P. Kitabgi, et al., [Mol. Pharm. 18, 11-19 (1980)] and the activity relationships of a series of NT analogs and their relative potencies has been explored by J. E. Rivier, et al. [J. Med. Chem., 20, No. 11, 1409-1412 (1977)]. Among their findings, J. E. Rivier, et al., observed that substitutions in positions 1-9 of the tridecapeptide yielded active peptides, but that modifications in positions 10-13 significantly decreased biological activity.
These references indicate that the smallest NT peptide fragment that exhibits NT activity is the C-terminal hexapeptide. Although the corresponding pentapeptide fragment exhibits NT-like activity, it is less potent then both NT itself and its hexapeptide fragment.